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MicroRNA-based methods and assays for osteocarcinoma

a microrna-based method and osteocarcinoma technology, applied in the direction of antineoplastic agents, organic active ingredients, drug compositions, etc., can solve the problems of no osteosarcoma targeted therapy and the survival rate has not improved

Active Publication Date: 2021-01-21
3 D MATRIX
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this survival rate has not improved over the last 10 years, and fully 40% of osteosarcoma patients die of their disease.
However, no targeted therapy is currently available for osteosarcoma.

Method used

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  • MicroRNA-based methods and assays for osteocarcinoma
  • MicroRNA-based methods and assays for osteocarcinoma
  • MicroRNA-based methods and assays for osteocarcinoma

Examples

Experimental program
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example 1

A Small Subset of Cells of Osteosarcoma Cell LineExpresses CD 133

[0171]Osteosarcoma cell lines SaOS2, HOS, U2OS, MNNG / HOS, MG63, 143B, and HuO9 were screened for markers of mesenchymal stem cells or neural stem cells that have been considered as the origin of sarcoma. Basu-Roy, U et al. (2011) Oncogene 31:2270-82; Kuhn, N Z et al, (2010) J. Cell. Physiol. 222:268-77, As a result, CD133, the structural homolog of prominin-1, was found in all cell lines at a small population ranging from 0.04% to 8.47%, whereas CD44 was found in a large population (FIG. 1). SaOS2, MNNG / HOS, and HOS were found to be particularly strong in their expression of CD133 (8.47, 8.13, and 7.69 percent, respectively).

[0172]Single-cell proliferation of freshly isolated cell population was observed using PKH dye, which is a fluorescent dye that binds to cell membranes and segregates in daughter cells after each cell division. Normally, PKH concentration decreases with each cell division, so that quiescent cells r...

example 2

CD133high Cells Exhibit Increased Drug Resistance, Invasiveness, and Tumorigenesis

[0175]Since drug resistance is one of the important properties of TICs, populations of CD133high and CD133low cells were observed in the treatment condition with doxorubicin (DOX), cisplatin (CDDP), and methotrexate (MTX), which are standard chemotherapeutics against osteosarcoma, CD133high cells were more resistant to these chemotherapeutics than CD133low cells (FIG. 4). Furthermore, CD133high cells exhibited higher capability of invasion than CD133low cells (FIG. 5). qRT-PCR of mRNA from freshly isolated CD133high and CD133low cells revealed that CD133high SaOS2 cells expressed enhanced levels of Oct3 / 4, Nanog, and Sox-2, which are transcription factors that play a critical role in maintenance of self-renewal and pluripotency of embryonic stem cells as well as CSCs or TICs (Livings, P P et al. (2009) Cancer Res. 69:5648-55; Basu-Roy U et al. (2011) Oncogene 31:2270-82); multidrug resistance transport...

example 3

High-Level Expression of CD133 Messenger RNA is a Marker for Poor Survival Rates of Osteosarcoma Patients

[0176]To evaluate the clinical importance of CD133, cell lines established from fresh human osteosarcoma biopsies were analyzed by flow cytometer and found to contain CD133high population at a rare frequency <10% (FIG. 8). Furthermore, a clinical study of 35 osteosarcoma patients revealed that high expression levels of CD133 messenger RNA (mRNA) correlated with significantly worse overall survival rates of osteosarcoma patients (log-rank lest, P=0.0262). Results are shown in FIG. 9 and Table 7.

TABLE 7Uni- and multivariate analyses and the relationship between clinicopathologic variables and CD133 expression in 35 casesNumber CorrelationofCD133CD133(CD133) χ2VariablecasesLowHigh(P value)Age (years)0.120 0-1076111-2025111421+312Gender0.164Male23149Female1248Site0.319Femur21129Tibia954Humerus211Other303Histology0.394Osteoblastic1697Chandroblastic642Fibroblastic202Other, NA*1156Metas...

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Abstract

Provided are methods and compositions useful in the diagnosis, treatment, and monitoring of osteosarcoma. Antisense to certain microRNA (miRNA) found to be associated with cancer stem cells (CSCs) or tumor-initiating cells (TICs) of osteosarcoma are useful to suppress tumor growth and metastasis, and prolong survival. Antisense oligonucleotides to miR-133a are synergistic in combination with standard chemotherapy such as cisplatin in the treatment of osteosarcoma.

Description

RELATED APPLICATIONS[0001]This application claims benefit of priority to U.S. Provisional Patent Application No. 61 / 531,942, filed Sep. 7, 2011, and U.S. Provisional Patent Application No. 61 / 696,981, filed Sep. 5, 2012.BACKGROUND OF THE INVENTION[0002]There is growing evidence that tumors contain a subset of cells with stern cell-like properties. These cells, often referred to either as “cancer stem cells” (CSCs) or as “tumor-initiating cells” (TICs), are responsible for forming the bulk of tumor. These CSCs possess both self-renewal and differentiation capabilities, and are believed to give rise to tumor heterogeneity. Furthermore, they have been shown to be associated with the most lethal characteristics of tumors—drug resistance and metastasis. The first evidence of the existence of CSCs came from studies of hematological malignancies in 1994. More recently, CSCs have been identified in a number of solid tumors, including breast, brain, skin, lung, colon, pancreatic, liver, head...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7105A61K31/282A61P35/00A61K31/7115
CPCA61K31/7105A61K31/282A61K45/06A61K31/7115A61P35/00A61K33/243A61K31/704A61K2300/00
Inventor OCHIYA, TAKAHIROFUJIWARA, TOMOHIRO
Owner 3 D MATRIX